Transferrin-mediated iron sequestration suggests a novel therapeutic strategy for controlling Nosema disease in the honey bee, Apis mellifera.

Nosemosis C, a Nosema disease caused by microsporidia parasite Nosema ceranae, is a significant disease burden of the European honey bee Apis mellifera which is one of the most economically important insect pollinators. Nevertheless, there is no effective treatment currently available for Nosema disease and the disease mechanisms underlying the pathological effects of N. ceranae infection in honey bees are poorly understood. Iron is an essential nutrient for growth and survival of hosts and pathogens alike. The iron tug-of-war between host and pathogen is a central battlefield at the host-pathogen interface which determines the outcome of an infection, however, has not been explored in honey bees. To fill the gap, we conducted a study to investigate the impact of N. ceranae infection on iron homeostasis in honey bees. The expression of transferrin, an iron binding and transporting protein that is one of the key players of iron homeostasis, in response to N. ceranae infection was analysed. Furthermore, the functional roles of transferrin in iron homeostasis and honey bee host immunity were characterized using an RNA interference (RNAi)-based method. The results showed that N. ceranae infection causes iron deficiency and upregulation of the A. mellifera transferrin (AmTsf) mRNA in honey bees, implying that higher expression of AmTsf allows N. ceranae to scavenge more iron from the host for its proliferation and survival. The suppressed expression levels of AmTsf via RNAi could lead to reduced N. ceranae transcription activity, alleviated iron loss, enhanced immunity, and improved survival of the infected bees. The intriguing multifunctionality of transferrin illustrated in this study is a significant contribution to the existing body of literature concerning iron homeostasis in insects. The uncovered functional role of transferrin on iron homeostasis, pathogen growth and honey bee's ability to mount immune responses may hold the key for the development of novel strategies to treat or prevent diseases in honey bees.

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.

The Phylogeny and Pathogenesis of Sacbrood Virus (SBV) Infection in European Honey Bees, Apis mellifera.

RNA viruses that contain single-stranded RNA genomes of positive sense make up the largest group of pathogens infecting honey bees. Sacbrood virus (SBV) is one of the most widely distributed honey bee viruses and infects the larvae of honey bees, resulting in failure to pupate and death. Among all of the viruses infecting honey bees, SBV has the greatest number of complete genomes isolated from both European honey bees Apis mellifera and Asian honey bees A. cerana worldwide. To enhance our understanding of the evolution and pathogenicity of SBV, in this study, we present the first report of whole genome sequences of two U.S. strains of SBV. The complete genome sequences of the two U.S. SBV strains were deposited in GenBank under accession numbers: MG545286.1 and MG545287.1. Both SBV strains show the typical genomic features of the Iflaviridae family. The phylogenetic analysis of the single polyprotein coding region of the U.S. strains, and other GenBank SBV submissions revealed that SBV strains split into two distinct lineages, possibly reflecting host affiliation. The phylogenetic analysis based on the 5'UTR revealed a monophyletic clade with the deep parts of the tree occupied by SBV strains from both A. cerane and A. mellifera, and the tips of branches of the tree occupied by SBV strains from A. mellifera. The study of the cold stress on the pathogenesis of the SBV infection showed that cold stress could have profound effects on sacbrood disease severity manifested by increased mortality of infected larvae. This result suggests that the high prevalence of sacbrood disease in early spring may be due to the fluctuating temperatures during the season. This study will contribute to a better understanding of the evolution and pathogenesis of SBV infection in honey bees, and have important epidemiological relevance.

Association of a Novel Diagnostic Biomarker, the Plasma Cardiac Bridging Integrator 1 Score, With Heart Failure With Preserved Ejection Fraction and Cardiovascular Hospitalization.

Importance: Transverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease. Objective: To determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF). Design, Setting, and Participants: In this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017. Main Outcomes and Measures: The analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations. Results: A total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P < .001). For patients with HFpEF, the CS outperforms NT-proBNP when the comparator group was either healthy control participants (CS: area under curve [AUC], 0.98 [95% CI, 0.96-1.00]; NT-proBNP level: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001) or those with risk factors (CS: AUC, 0.98 [95% CI, 0.97-1.00]; NT-proBNP: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001). Kaplan-Meier analysis of 1-year cardiovascular hospitalizations adjusted for age, sex, body mass index, and NT-proBNP levels reveals that patients with HFpEF with CS greater than or equal to 1.80 have a hazard ratio of 3.8 (95% CI, 1.3-11.2; P = .02) for hospitalizations compared with those with scores less than 1.80. Conclusions and Relevance: If further validated, the plasma CS, a marker of transverse tubule dysfunction, may serve as a biomarker of cardiomyocyte remodeling that has the potential to aide in the diagnosis of HFpEF.

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

INTRODUCTION: Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. AREAS COVERED: Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. EXPERT OPINION: The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

Marijuana and Listing for Heart Transplant: A Survey of Transplant Providers.

BACKGROUND: There is no consensus within the heart transplant community about whether patients who use marijuana should be eligible for transplant listing, but several states have passed legislation prohibiting marijuana-using patients from being denied transplant listing based on their use of the substance. METHODS AND RESULTS: We conducted an independent, voluntary, web-based survey of heart and lung transplant providers to assess current practice patterns and attitudes toward marijuana use in patients with advanced heart failure being considered for transplant. A total of 360 heart transplant providers responded from 26 countries. Nearly two thirds of respondents (n=222, 64.4%) supported listing patients with advanced, end-stage heart failure for transplant who use legal medical marijuana. Significantly, fewer respondents (n=96, 27.5%) supported transplant listing for patients using legal recreational marijuana. The majority of providers currently make patients eligible for transplantation after a period of abstinence from marijuana (n=241, 68.3%). There were no differences between the proportion of respondents supporting transplant listing after stratification by profession or country/region. Most (78.4%) survey respondents from states with laws prohibiting marijuana-using patients from being denied transplant listing reported denying all marijuana-using patients or mandating abstinence before transplant listing. CONCLUSIONS: The majority of heart and lung transplant providers in our study sample supports the listing of patients who use medical marijuana for transplant after a period of abstinence. Communication and collaboration between the medical community and legislative groups about marijuana use in transplant candidates is needed to ensure the best patient outcomes with the use of scarce donor organs.

Adaptive B cell responses in rituximab-treated diffuse large B cell lymphoma patients during complete remission.

Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen. Treatment using rituximab in combination with chemotherapy has dramatically improved overall survival rate of diffuse large B cell lymphoma (DLBCL). Since rituximab can deplete both lymphoma B cells and normal B cells, how rituximab-treatment affects normal B cell function in DLBCL patients under remission is unclear. Here, we examined peripheral blood B cell composition and antigen-specific B cell responses in DLBCL patients in remission and observed reductions in the frequencies of total B cell as well as several major B cell subsets, including CD19(+)IgD(+) naive B cells, CD19(+)IgD(-)CD27(+) memory B cells, and CD19(lo)CD27(hi) plasmablasts. Moreover, tetanus toxin (TT)-specific B cell proliferation was reduced in DLBCL patients in remission. On the other hand, HA-specific IgG-secreting B cell responses could be stimulated by influenza vaccination in DLBCL patients in remission, demonstrating that the machinery for generating de novo adaptive B cell responses was functional in DLBCL patients in remission. Our results provided insights in normal B cell function in DLBCL patients in remission.

Regulation of HBV-specific CD8(+) T cell-mediated inflammation is diversified in different clinical presentations of HBV infection.

Chronic HBV infection is the leading cause of liver cirrhosis and hepatic cancer, but the individual responses toward HBV infection are highly variable, ranging from asymptomatic to chronic active hepatitis B inflammation. In this study, we hypothesized that the different individual responses to HBV infection was associated with differences in HBV-specific CD8(+) T cell-mediated inflammation and cytotoxicity. Blood samples were collected from subjects with asymptomatic HBV-infection, subjects undergoing active chronic HBV flares (active CHB), and subjects with HBV-infected hepatocellular carcinoma (HBV-HCC). By tetramer staining, we found that all three groups had similar frequencies of HBVspecific CD8(+) T cells. However, after HBV peptide stimulation, the HBV-specific CD8(+) T cells in asymptomatic subjects had significantly stronger interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and CD107a expression than those in active CHB and HBV-HCC patients. Examination of surface marker expression revealed that the PD-1(-)Tim-3(-) double-negative cell population was the main contributor to HBV-specific inflammation. In active CHB patients and HBV-HCC patients, however, the frequencies of activated PD-1(-)Tim-3(-) cells were significantly reduced. Moreover, the serum HBV DNA titer was not correlated with the frequencies of HBV-specific CD8(+) T cells but was inversely correlated with the frequencies of IFN-g-expressing and CD107a-express cells in response to HBV stimulation. Together, our data demonstrated that the status of HBVspecific CD8(+) T cell exhaustion was associated with different clinical outcomes of chronic HBV infection.

Tricuspid Regurgitation, the Forgotten Valvular Lesion-A Contemporary Review of Etiology, Prevalence, and Management Options.

Tricuspid regurgitation (TR) is a common finding. Pathologic TR is an independent risk factor for mortality. TR can be classified by etiology into functional versus organic. Organic TR is caused by structural damage to the tricuspid valve (TV) by a spectrum of etiologies, including pacemaker leads and right heart biopsies, whereas functional TR is predominantly due to elevated pulmonary pressures. Atrial fibrillation and chamber enlargement, among other risk factors, are strong predictors of functional TR. Correction of elevated pulmonary pressures improves TR, and concurrent repair of severe TR at the time of left heart valve surgery improves postoperative heart failure symptoms but does not improve survival. TR repair is associated with less operative and long-term mortality than TV replacement, and demonstrates similar improvements in heart failure symptoms. Substantial residual TR remains after repair, and reoperative mortality for residual TR is considerable. Percutaneous TV replacement may offer a rescue strategy.

Systemic spread and propagation of a plant-pathogenic virus in European honeybees, Apis mellifera.

UNLABELLED: Emerging and reemerging diseases that result from pathogen host shifts are a threat to the health of humans and their domesticates. RNA viruses have extremely high mutation rates and thus represent a significant source of these infectious diseases. In the present study, we showed that a plant-pathogenic RNA virus, tobacco ringspot virus (TRSV), could replicate and produce virions in honeybees, Apis mellifera, resulting in infections that were found throughout the entire body. Additionally, we showed that TRSV-infected individuals were continually present in some monitored colonies. While intracellular life cycle, species-level genetic variation, and pathogenesis of the virus in honeybee hosts remain to be determined, the increasing prevalence of TRSV in conjunction with other bee viruses from spring toward winter in infected colonies was associated with gradual decline of host populations and winter colony collapse, suggesting the negative impact of the virus on colony survival. Furthermore, we showed that TRSV was also found in ectoparasitic Varroa mites that feed on bee hemolymph, but in those instances the virus was restricted to the gastric cecum of Varroa mites, suggesting that Varroa mites may facilitate the spread of TRSV in bees but do not experience systemic invasion. Finally, our phylogenetic analysis revealed that TRSV isolates from bees, bee pollen, and Varroa mites clustered together, forming a monophyletic clade. The tree topology indicated that the TRSVs from arthropod hosts shared a common ancestor with those from plant hosts and subsequently evolved as a distinct lineage after transkingdom host alteration. This study represents a unique example of viruses with host ranges spanning both the plant and animal kingdoms. IMPORTANCE: Pathogen host shifts represent a major source of new infectious diseases. Here we provide evidence that a pollen-borne plant virus, tobacco ringspot virus (TRSV), also replicates in honeybees and that the virus systemically invades and replicates in different body parts. In addition, the virus was detected inside the body of parasitic Varroa mites, which consume bee hemolymph, suggesting that Varroa mites may play a role in facilitating the spread of the virus in bee colonies. This study represents the first evidence that honeybees exposed to virus-contaminated pollen could also be infected and raises awareness of potential risks of new viral disease emergence due to host shift events. About 5% of known plant viruses are pollen transmitted, and these are potential sources of future host-jumping viruses. The findings from this study showcase the need for increased surveillance for potential host-jumping events as an integrated part of insect pollinator management programs.

Failing the failing heart: a review of palliative care in heart failure.

Heart failure (HF) is the most common reason for hospital admission for patients older than 65 years. With an aging population and improving survival in heart failure patients, the number of people living with HF continues to grow. As this population increases, the importance of treating symptoms of fatigue, dyspnea, pain, and depression that diminish the quality of life in HF patients becomes increasingly important. Palliative care has been shown to help alleviate these symptoms and improve patients' satisfaction with the care they receive. Despite this growing body of evidence, palliative care consultation remains underutilized and is not standard practice in the management of HF. With an emphasis on communication, symptom management, and coordinated care, palliative care provides an integrated approach to support patients and families with chronic illnesses. Early communication with patients and families regarding the unpredictable nature of HF and the increased risk of sudden cardiac death enables discussions around advanced care directives, health care proxies, and deactivation of permanent pacemakers or implantable cardioverter defibrillators. Cardiologists and primary care physicians who are comfortable initiating these discussions are encouraged to do so; however, many fear destroying hope and are uncertain how to discuss end-of-life issues. Thus, in order to facilitate these discussions and establish an appropriate relationship, we recommend that patients and families be introduced to a palliative care team at the earliest appropriate time after diagnosis.

Intact skeletal muscle mitochondrial enzyme activity but diminished exercise capacity in advanced heart failure patients on optimal medical and device therapy.

BACKGROUND: A skeletal myopathy, perhaps attributable to neuro-endocrine excitation or disuse, has been described in heart failure (HF) patients, and is thought to contribute to their exercise limitation. Our purpose was to assess biochemical and morphometric characteristics of skeletal muscles of HF patients on optimal HF therapy. A secondary purpose was to explore the effects of clonidine, which interrupts the neuro-endocrine excitation, on these same muscle characteristics. METHODS AND RESULTS: Eleven HF patients (50.8 ± 3.4 years, peak VO2 11.6 ± 2.5 ml/kg/min) underwent two vastus lateralis biopsies (pre/post clonidine). Baseline values were compared to biopsies in 11 age-matched, healthy controls. Scatter plots of individual values for each mitochondrial enzyme revealed almost complete overlap between HF and control groups; mean values, although tending to be greater in controls versus HF patients, were not significantly different. The proportion of type 1 fibers was diminished in 10 of 11 patients. There was no difference in any of the variables after 3 months clonidine versus placebo. CONCLUSION: In HF patients treated with optimal medical and device therapy, characteristic abnormalities of mitochondrial enzyme activity are not found, but muscle fiber type shifts are present. The remaining severe impairment in exercise capacity cannot be attributed to mitochondrial abnormalities.

The natural history of biopsy-negative rejection after heart transplantation.

Purpose. The most recent International Society for Heart and Lung Transplantation (ISHLT) biopsy scale classifies cellular and antibody-mediated rejections. However, there are cases with acute decline in left ventricular ejection fraction (LVEF ≤ 45%) but no evidence of rejection on biopsy. Characteristics and treatment response of this biopsy negative rejection (BNR) have yet to be elucidated. Methods. Between 2002 and 2012, we found 12 cases of BNR in 11 heart transplant patients as previously defined. One of the 11 patients was treated a second time for BNR. Characteristics and response to treatment were noted. Results. 12 cases (of 11 patients) were reviewed and 11 occurred during the first year after transplant. 8 cases without heart failure symptoms were treated with an oral corticosteroids bolus and taper or intravenous immunoglobulin. Four cases with heart failure symptoms were treated with thymoglobulin, intravenous immunoglobulin, and intravenous methylprednisolone followed by an oral corticosteroids bolus and taper. Overall, 7 cases resulted in return to normal left ventricular function within a mean of 14 ± 10 days from the initial biopsy. Conclusion. BNR includes cardiac dysfunction and can be a severe form of rejection. Characteristics of these cases of rejection are described with most cases responding to appropriate therapy.

Abnormalities of calcium handling proteins in skeletal muscle mirror those of the heart in humans with heart failure: a shared mechanism?

BACKGROUND: In the failing human heart, abnormalities of Ca(2+) cycling have been described, but there is scant knowledge about Ca(2+) handling in the skeletal muscle of humans with heart failure (HF). We tested the hypothesis that in humans with HF, Ca(2+) cycling proteins in skeletal muscle are abnormal. METHODS AND RESULTS: Ten advanced HF patients (50.4 ± 3.7 years), and 9 age-matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a, which is responsible for Ca(2+) sequestration into the sarcoplasmic reticulum(SR), was lower in HF versus controls (4.8 ± 0.5 vs 7.5 ± 0.8 AU, P = .01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF versus controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8 ± 0.1 vs 3.9 ± 0.9 AU, P = .004). Dihydropyridine receptors were reduced in HF, (2.1 ± 0.4 vs 3.6 ± 0.5 AU, P = .04). We tested the hypothesis that these abnormalities of Ca(2+) handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients. CONCLUSION: In chronic HF, marked abnormalities of Ca(2+) handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca(2+)-calmodulin-dependent-protein kinase II.

Lung transplantation and coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) remains a relative contraindication to lung transplantation. We have offered lung transplantation and coronary revascularization to selected patients with discrete CAD and preserved left ventricular function. The purpose of this report is the following: (1) to examine the short-term and medium-term outcome of patients after coronary revascularization and lung transplantation; and (2) to compare the short-term and medium-term outcome of this cohort to a matched group of lung transplant recipients without CAD. METHODS: From January 2000 to March 2010, 27 patients with CAD underwent coronary revascularization and lung transplantation. The control group was matched based on age, diagnosis, lung allocation score, and type of procedure. RESULTS: Lung transplant recipients with CAD and the control group had similar incidence of primary graft dysfunction (grade III). The duration of mechanical ventilation, intensive care unit stay, and hospital stay were the same. At a mean follow-up of 3 years, the incidence of composite adverse cardiac events was similar in the 2 groups. CONCLUSIONS: Lung transplant recipients with CAD and the control group also had similar medium-term survival. Lung transplantation can be considered in patients with preexistent CAD with acceptable early and medium-term outcomes.

Long-term outcomes of heart transplantation in older recipients.

BACKGROUND: Heart transplantation in the elderly is increasingly common. In the mid-1990s, 25% of recipients in our program were >62 years of age. We evaluated outcomes from one institution with the hypothesis that older recipients may be at higher risk of major complications associated with immunosuppression. METHODS: We analyzed results for 182 patients aged 62 to 75 years (mean +/- SD: 66.3 +/- 11.4 years) who underwent heart transplantation between January 1995 and July 2001 at a single institution. They were compared with a control group of 348 contemporaneous adult recipients aged 18 to 62 years (mean +/- SD: 48.2 +/- 11.4 years). All recipients in this consecutive cohort had a follow-up of at least at least 5 years. End-points studied were Kaplan-Meier survival, freedom from dialysis and freedom from malignancy at 100 months. Follow-up was 100% at 100 months. RESULTS: At 100 months, survival for the elderly was 55% (46 remaining at risk) and 63% (102 remaining at risk) for controls (p = 0.051, log-rank test). Re-transplant and dialysis, but not recipient age or malignancy, were predictive of survival by regression analysis (p = 0.003, p < 0.001, p = 0.53 and p = 0.84, respectively). Freedom from malignancy at 100 months was 68% for the elderly and 95% for controls (p < 0.001). Age predicted malignancy by regression analysis (p < 0.001). At 100 months, freedom from dialysis was 81% for the elderly and 87% for controls (p = 0.005). Pre-operative creatinine, but not age, was predictive of need for dialysis (p = 0.003 and p = 0.47, respectively). CONCLUSIONS: Although long-term survival of older heart transplant recipients is acceptable, it is significantly lower than in young recipients. The increased risk of renal failure and malignancy among elderly patients likely influences the difference in survival observed between the two groups. Pre-operative renal function warrants careful consideration. As ventricular assist device technology improves, it may be used to complement heart transplantation to avoid immunosuppression and its side effect of malignancy in older patients with advanced heart failure.